The present invention relates to novel cosmetic and/or dermatological compositions, in particular compositions intended for skincare and comprising at least one compound of the retinoid family. More particularly, the invention relates to stable compositions comprising at least one compound of the retinoid family and at least one histidine derivative.
Cosmetic and/or dermatological compositions based on retinoids have undergone considerable development in recent years. Among the retinoids, the use of retinoic acid in compositions for treating acne is well known.
However, it has been recognized that other derivatives of the retinoid family offer an advantage, both for treating acne and for skincare, in particular for limiting, or even eliminating, the effects of ageing on the skin: wrinkles, a weatherbeaten appearance, yellowing, the loss of elasticity, redness, dryness and the appearance of marks are the usual manifestations of ageing of the skin. These manifestations are proportionately more pronounced when the skin has been frequently exposed to the sun or is particularly sensitive to exposure to UV radiation.
Thus, the effects of intrinsic ageing of the skin (associated with age) and of light-induced ageing (due to exposure to the sun) can be cumulative. The manifestations of ageing usually appear at an advanced age; however, their prevention should be undertaken from the start of adult life, by means of appropriate care measures.
Treatment of the skin with derivatives of the retinoid family forms a part of these preventive or curative measures for caring for the manifestations of ageing, namely: wrinkles, weatherbeaten skin, yellowing, loss of elasticity, redness, dryness and marks.
Among the derivatives of the retinoid family, retinol, also known as vitamin A, and esterified derivatives of retinol are most particularly advantageous. In point of fact, retinol is a natural endogenous constituent of the human body. It is well tolerated when applied to the skin, up to levels much higher than those for retinoic acid. Retinol esters are converted into retinol by the human body.
However, when they are introduced into a cosmetic or dermatological composition intended for topical application, retinol and its esters rapidly degrade, under the effect of light, oxygen, metal ions, oxidizing agents, water or, in particular, under the effect of an increase in temperature. The thermal degradation of retinol was the subject of a study published in J. Soc. Cosm. Chem. 46, 191-198 (July-August 1995).
Various combinations of retinol or of other derivatives of the retinoid family with antioxidants are known, the retinoids being of improved stability in these combinations:
WO 93/00085 describes W/O emulsions comprising retinol and a stabilizing system consisting of a chelating agent such as, for example, EDTA, and an antioxidant which can be either a liposoluble antioxidant, for instance butyl hydroxytoluene (BHT) or vitamin E, or a water-soluble antioxidant, for instance vitamin C. According to this publication, W/O emulsions containing retinol stabilized with a system consisting of a liposoluble antioxidant and a water-soluble antioxidant can also be prepared.
EP 608,433 describes compositions containing retinol and a stabilizer chosen from chelating agents and polysaccharides, oils with an iodine number of greater than 70, polyethylene (propylene) glycols, hydroxycarboxylic acid salts, neutral amino acid salts, liposoluble antioxidants combined with EDTA and a benzophenone, liposoluble antioxidants combined with an acidic compound and a benzophenone, cyclodextrin derivatives in which an antioxidant or a UV screening agent is included, butanediol and/or liposoluble antioxidants, water-soluble benzophenone derivatives, basic amino acids and their salts, acidic amino acids and their salts, polar oils and hydrophilic mineral clays.
Lastly, the use of N-acyl carnosine and histidine derivatives as antioxidants, in particular as inhibitors of the formation of lipid peroxides, in the presence of which retinol is known to be unstable, is known from EP 500,332 and from the publication xe2x80x9cAntioxidant and Emulsifying Activity of N-(long-chain-acyl) histidine and N-(long-chain-acyl) carnosinexe2x80x9d, Hironobu Murase, J. Agric. Food Chem., Vol. 41, 1993, pp. 1601-1604.
However, none of these compounds whether they are described as antioxidants or more specifically as retinoid stabilizers, allow satisfactory stabilization of retinoids to be obtained. Accordingly, there remains a need for compositions containing retinoids which are stabilized from thermal degradation.
An object of the present invention is to provide compositions containing one or more retinoids, in which the retinoids have enhanced resistance to thermal degradation.
It is another object of the present invention to provide methods of enhancing the resistance of retinoids to thermal degradation.
The inventors have now discovered, surprisingly, that the combination of a retinoid chosen from vitamin A (or retinol) and bioconvertible precursors of vitamin A, with certain histidine derivatives, makes it possible to avoid the degradation, in particular the thermal degradation, of these retinoids. Thus, these retinoids can be introduced into cosmetic and/or dermatological compositions and can be stored for several months, without their efficiency being degraded.
Accordingly, the objects of the present invention, and others, may be accomplished with a composition containing:
(a) at least one retinoid chosen from: vitamin A (or retinol), retinal and bioconvertible precursors of vitamin A, and
(b) at least one histidine derivative represented by formula (I) below: 
wherein
n is an integer ranging from 0 to 5,
nxe2x80x2 is an integer ranging from 1 to 16,
R represents a side chain of an amino acid,
X represents a radical chosen from the radicals of formulae, read from left to right:
xe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94COxe2x80x94,
Rxe2x80x2 represents a linear or branched, saturated or unsaturated, optionally hydroxylated, C6 to C22 alkyl radical or C6 to C22 aminoalkyl radical, the amine function optionally being protected in the form of acetamide or substituted with one or two lower alkyl groups, with the proviso that Rxe2x80x2 is an aminoalkyl radical as defined above when X=xe2x80x94COxe2x80x94
Q+ represents H+ or an organic or inorganic cation,
as well as the addition salts of a compound of formula (I) with an organic or inorganic acid.
The term vitamin A means retinol of all-trans type or of 13-cis type.
The expression xe2x80x9cbioconvertible precursor of vitamin Axe2x80x9d denotes any compound which can be converted into vitamin A by the human body. Among these compounds, mention may be made of retinol esters, in particular C1-C6 esters which are very rapidly degraded into retinol by the human body. Among the retinol esters, retinyl acetate and retinyl propionate are more particularly intended.
A subject of the invention is also a cosmetic or dermatological composition comprising the combination as described above and at least one physiologically acceptable support.
A subject of the invention is also the use of at least one histidine derivative of formula (I), as defined above, for improving the stability of a composition comprising a retinoid chosen from vitamin A (or retinol), retinal and bioconvertible precursors of vitamin A.
A subject of the invention is also a process for improving the stability of a composition comprising a retinoid chosen from vitamin A (or retinol), retinal and bioconvertible precursors of vitamin A, this process consisting in combining an effective amount of at least one histidine derivative of formula (I), as defined above, with the said retinoid.
The expression xe2x80x9ceffective amount of histidine derivative of formula (I)xe2x80x9d means an amount which is sufficient to obtain an appreciable and significant improvement in the thermal stability of the retinoid(s) contained in the composition. This minimum amount of stabilizer to be used, which can vary depending on the nature of the physiologically acceptable support selected for the composition, can be determined without difficulty by means of a test for measuring thermal stability, such as the one given in the examples below.
Thus, another subject of the invention is the use of the combination of at least one retinoid chosen from vitamin A (or retinol), retinal and bioconvertible precursors of vitamin A and of at least one histidine derivative of formula (I), in, or for the preparation of, a composition intended for dermatological treatment for controlling and/or preventing irritation, inflammation, immunosuppression and/or acne.
A subject of the invention is also a cosmetic treatment process which consists in controlling the signs of ageing, particularly the signs of ageing induced by photoperoxidation, in particular the photoperoxidation of squalene and/or collagen, by topical application to the skin and/or the scalp and/or the hair of a composition comprising at least one retinoid chosen from vitamin A (or retinol), retinal and bioconvertible precursors of vitamin A, and at least one histidine derivative of formula (I) according to the invention. A subject of the invention is also the use of such a cosmetic composition for controlling and/or preventing the signs of light-induced ageing of the skin and/or the hair. A subject of the invention is also a dermatological composition comprising a combination according to the invention, which is intended for controlling the signs of ageing of the skin or the hair, particularly the signs of ageing induced by photoperoxidation, in particular the photoperoxidation of squalene and/or collagen.
A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following detailed description.
The pH of the composition according to the invention is preferably greater than or equal to 6, preferably greater than or equal to 7. The pH of the composition according to the invention is generally less than or equal to 12, preferably less than or equal to 10. These pH ranges include all specific values and subranges therebetween, including pH 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0 and 11.5.
The organic cation (Q+) of the histidine derivatives of formula (I) may be chosen from ammoniums containing a residue chosen from basic amino acids such as lysine or arginine, or alternatively from amino alcohols such as glucamine, N-methylglucamine or 3-amino-1,2-propanediol.
The inorganic cation (Q+) may be chosen from alkali metal or alkaline-earth metal salts such as Na+ or K+, or can be the NH4+ ion.
The addition salts with an acid may be chosen, for example, from the hydrochlorides, hydrobromides, sulphates, tartrates and acetates.
The compounds of formula (I) include at least one asymmetric carbon in their structure: the invention relates equally to the compounds of D configuration, of L configuration and to mixtures thereof, in particular the racemic mixture of the D and L compounds.
The preferred compounds of formula (I) have at least one of the following characteristics:
Rxe2x80x2 preferably denotes a linear or branched, saturated alkyl radical containing from 8 to 18 carbon atoms,
n is an integer from 1 to 5, and
nxe2x80x2 is an integer ranging from 1 to 11.
Among the linear or branched alkyl radicals containing from 6 to 22 carbon atoms, preferable examples include hexyl, octyl, nonyl, 2-ethylhexyl, dodecyl, hexadecyl and octadecyl radicals.
The lower alkyl groups generally comprise from 1 to 6 carbon atoms. Lower alkyl groups which may be mentioned are methyl, ethyl, propyl, isopropyl, tert-butyl and hexyl radicals.
Among the linear alkyl radicals containing from 6 to 22 carbon atoms which may be mentioned in particular are octyl, dodecyl, hexadecyl and octadecyl radicals.
Among the branched alkyl radicals containing from 6 to 22 carbon atoms, mention may be made in particular of 2-methylpentyl, 1-methylhexyl and 3-methylheptyl radicals.
The expression xe2x80x9cunsaturated alkyl radicalxe2x80x9d preferably refers to a linear or branched radical containing from 6 to 22 carbon atoms comprising one or more double bonds.
The amino acid side chains correspond to the side chains of any of the natural amino acids. Thus, R can in particular represent hydrogen or a methyl or isopropyl radical. These can thus be non-polar side chains, polar but uncharged side chains and negatively or positively charged side chains.
An exemplary process for preparing the compounds of formula (I) comprises the step which consists in reacting with histidine, in an inert solvent, a compound of formula (II) 
in which nxe2x80x2, n, R, Rxe2x80x2 and X have the same meanings as in formula (I) above, and Y is a conventional activating group for the acid function.
The reactions for activating acid groups xe2x80x94COOH are well known to those skilled in the art. See for example, to xe2x80x9cAdvanced Organic Chemistry, Jerry March, 3rd Edition, 1985, pp. 370-377xe2x80x9d, incorporated herein by reference. The term xe2x80x9ccoupling agentxe2x80x9d refers to any compound capable of substituting the OH group in the compound of formula (IV), and then of subsequently being substituted with the amino acid which it is desired to graft, for example histidine. Coupling agents are described in xe2x80x9cAdvanced Organic Chemistry, J. March, 3rd Edition, 1985, page 372xe2x80x9d, incorporated herein by reference. 2-(5-Norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate can be used in particular as a coupling agent.
The starting histidine comprising an asymmetric carbon is used in pure optical form or as a mixture (D; L; D,L) depending on the desired optical form of the compound of formula (I).
Dichloromethane, 1,2-dichloroethane, 1,1,1-trichloroethane, chloroform, acetonitrile, toluene, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, cyclohexane, dimethylformamide, water or a mixture of these solvents can be used as solvent.
The reaction is carried out at a temperature preferably of between xe2x88x9210xc2x0 C. and +40xc2x0 C. and more preferably of between 20xc2x0 C. and 30xc2x0 C.
The reaction can be carried out in the presence of a base. This can be chosen from alkali metal or alkaline-earth metal hydroxides, sodium hydrogen carbonate, alkali metal alkoxides, alkaline hydrides, tertiary amines such as pyridine, diisopropylethylamine or triethylamine. Sodium hydrogen carbonate is preferably used.
The preferred compounds corresponding to the general formula (I) are those which are chosen from the following formulae: 
wherein
x is an integer ranging from 6 to 22 and Q+ being as defined above, and 
wherein
Rxe2x80x2, X, Q+ and nxe2x80x2 are as described above.
The compounds of formula (Ia) are as described in French patent application serial No. 98/03150 filed on Mar. 13, 1998, incorporated herein by reference.
The compounds of formula (Ib) are in particular as described in French patent application Ser. No. 96/14880 filed on Dec. 4, 1998, and incorporated herein by reference.
The compounds of formula (Ia) are obtained by a process which consists in reacting with histidine, in an inert solvent, a compound of formula (II)
Rxe2x80x3NHxe2x80x94(CH2)xxe2x80x94COOHxe2x80x83xe2x80x83(II)
in which n has the same meaning as in formula (I) above, Rxe2x80x3 represents a protecting group for the amine function, the acid function of the compound (II) being activated, for example in the presence of a coupling agent.
The compounds of formula (Ib), when X represents xe2x80x94Oxe2x80x94COxe2x80x94, are obtained by a process which consists in reacting, in an inert solvent, a compound of formula (II) 
Xxe2x80x2 representing a halogen atom, in particular a chlorine atom, or a radical derived from an azole, in particular a radical obtained from an imidazole such as that of formula (III): 
and Rxe2x80x2 having the same meaning indicated in formula (Ib) above,
either (A) with carnosine,
or (B), in a first step, with an amino acid of formula:
H2Hxe2x80x94(CH2)nxe2x80x2xe2x80x94COOH
xe2x80x83to form a compound of formula (IV) below: 
Rxe2x80x2 and nxe2x80x2 having the same meanings as those given in formula (I) defined above, and, in a second step, in reacting histidine with the compound of formula (IV), in the presence of a coupling agent.
Examples of preferred compounds corresponding to the general formula (I) include:
N-octyloxycarbonyl-xcex2-alanyl-L-histidine (compound 1),
N-dodecyloxycarbonyl-xcex2-alanyl-L-histidine (compound 2),
N-(12-amino-1-oxododecyl)-L-histidine (compound 3),
N-2-ethylhexyloxycarbonyl-xcex2-alanyl-L-histidine hydrochloride,
N-hexadecyloxycarbonyl-xcex2-alanyl-L-histidine,
N-octylaminocarbonyl-xcex2-alanyl-L-histidine,
N-dodecylaminocarbonyl-xcex2-alanyl-L-histidine,
N-dodecylsulphonyl-xcex2-alanyl-L-histidine,
N-dodecylamino-oxalyl-xcex2-alanyl-L-histidine.
One skilled in the art will be able, by means of simple tests, to adapt the relative proportion of retinoid and of histidine derivatives of formula (I) to obtain the desired effect. The optimum proportions of the various constituents can vary, for example as a function of the molecular weight of the polymer, the content of amines and/or the content of tertiary amines in this polymer.
Besides the retinoid and the histidine derivative of formula (I), the composition according to the invention preferably comprises at least one sunscreen. The addition of a sunscreen makes it possible to reinforce the stability of the combination of the retinoid with the polyamino polymer, by limiting the harmful action of UV on the retinoid. Such a constituent can be chosen from the known families of hydrophilic or lypophilic sunscreens which are active in the UVA and/or UVB range. Mention may be made, for example, of: cinnamic derivatives such as, for example, 2-ethylhexyl p-methoxycinnamate, salicylic derivatives such as, for example, 2-ethylhexyl salicylate and homomenthyl salicylate, camphor derivatives such as, for example, 3-(4-methylbenzylidene)camphor, triazine derivatives such as 2,4,6-tris[p-(2xe2x80x2-ethylhexyl-1xe2x80x2-oxycarbonyl)anilino]-1,3,5-triazine, benzophenone derivatives such as 2-hydroxy-4-methoxybenzophenone, dibenzoylmethane derivatives such as 4-tert-butyl-4xe2x80x2-methoxydibenzoylmethane, xcex2,xcex2-diphenylacrylate derivatives such as 2-ethylhexyl xcex1-cyano-xcex2,xcex2-diphenylacrylate, p-aminobenzoic acid derivatives such as, for example, octyl para-dimethylaminobenzoate, menthyl anthranilate, the screening polymers and screening silicones described in WO 93/04665, incorporated herein by reference, and hydrophilic screening agents containing at least one sulphonic radical xe2x80x94SO3H, such as, for example, 2-phenylbenzimidazole-5-sulphonic acid or benzene-1,4-bis(3-methylidene-10-camphorsulphonic acid).
Another compound known as a retinol stabilizer can also be incorporated into the inventive composition. Examples of these compounds include chelating agents, and polysaccharides, oils with an iodine number of greater than or equal to 70, polyethylene glycols and/or polypropylene glycols, hydroxycarboxylates, amino acids and their salts, antioxidants such as butyl hydroxytoluene, butyl hydroxyanisole, xcex1, xcex2, xcex3 and xcex4-tocopherols, nordihydrogaiaretine, propyl gallate, fatty acid esters of vitamin C, ascorbic acid, ascorbic acid salts, isoascorbic acid, isoascorbic acid salts, sorbic acid, sorbic acid salts, butanediol, fatty acid esters of pentaerythritol, fatty esters of trimethylolpropane and hydrophilic mineral clays. Such compounds are known as retinoid stabilizers, see EP-A-608,433, incorporated herein by reference.
In the specific case of the treatment of acne, at least one specific antiacne, antiseborrhoeic and/or antibacterial agent, and in particular piroctone olamine sold under the name Octopirox by Hoechst, can also advantageously be incorporated into the composition.
In the compositions according to the invention, the retinoid is preferably introduced in an amount ranging from 0.0001 to 10% by weight relative to the total weight of the composition, advantageously from 0.001 to 3% and even more preferably from 0.01 to 1%. These weight % ranges include all specific values and subranges therebetween, such as 0.1, 0.2, 0.5, 2, 3, 5 and 8% by weight.
In the compositions according to the invention, the histidine derivative of formula (I) is preferably introduced in an amount ranging from 0.001 to 20% by weight relative to the total weight of the composition, advantageously from 0.05 to 10%. These weight % ranges include all specific values and subranges therebetween, such as 0.01, 0.1, 0.5, 1, 2, 5, 15 and 18% by weight.
The compositions of the invention can also comprise cosmetic or dermatological adjuvants chosen from fatty substances, organic solvents, emulsifiers, nonionic thickeners, softeners, antioxidants, opacifiers, stabilizers, silicones, antifoaming agents, moisturizers, vitamins, fragrances, preserving agents, surfactants, preferably nonionic surfactants, fillers, sequestering agents, polymers other than those described above, propellants, acidifying or basifying agents, dyes or any other ingredient commonly used in cosmetics.
The fatty substances can consist of an oil or a wax or a mixture thereof, petroleum jelly, paraffin, lanolin, hydrogenated lanolin or acetylated lanolin; they also comprise fatty acids, fatty alcohols such as lauryl alcohol, cetyl alcohol, myristyl alcohol, stearyl alcohol, palmityl alcohol or oleyl alcohol, as well as 2-octyldodecanol, fatty acid esters such as glyceryl monostearate, polyethylene glycol monostearate, isopropyl myristate, isopropyl adipate, isopropyl palmitate, octyl palmitate, benzoates of C12-C15 fatty alcohols (Finsolv TN from Finetex), myristyl alcohol polyoxypropylenated with 3 mol of propylene oxide (Witconol APM from Witco), and triglycerides of C6-C18 fatty acids such as caprylic/capric acid triglycerides.
Among the oils which can be used in the present invention, mention may be made of mink oil, turtle oil, soybean oil, grapeseed oil, sesame oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil, avocado oil, olive oil, castor oil, jojoba oil, groundnut oil, hydrocarbon oils such as liquid paraffins, squalene and petroleum jelly; esters such as isopropyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, isononyl isononanoate, 2-ethylhexyl palmitate, 2-hexyldecyl laurate, 2-octyldecyl palmitate, 2-octyldodecyl myristate, 2-diethylhexyl succinate, diisostearyl malate, 2-octyldodecyl lactate and glyceryl triisostearate; silicone oils such as polymethylsiloxanes, polymethylphenylsiloxanes, polysiloxanes modified with fatty acids, polysiloxanes modified with fatty alcohols, polysiloxanes modified with polyoxyalkylenes, and fluorosilicones; perfluoro and/or organofluorine oils; higher fatty acids such as myristic acid, capric acid, caprylic acid, palmitic acid, stearic acid, behenic acid, oleic acid, linoleic acid, linolenic acid and isostearic acid, and higher fatty alcohols such as cetanol, stearyl alcohol and oleyl alcohol.
The waxes may be animal, plant, mineral or synthetic waxes. Among the animal waxes, mention may be made in particular of beeswaxes and whale wax. Among the plant waxes, mention may be made, inter alia, of carnauba wax, candelilla wax, ouricury wax, cork fibre waxes, sugarcane waxes and Japan waxes. Among the mineral waxes, mention may be made, in particular, of paraffin waxes, lanolin, microcrystalline waxes, lignite waxes and ozokerites. Among the synthetic waxes, mention may be made, in particular, of polyethylene waxes and the waxes obtained by Fisher-Tropsch synthesis. All these waxes are well known to those skilled in the art.
Among the organic solvents, mention may be made of lower alcohols and polyols such as ethanol, isopropanol, propylene glycol, glycerol and sorbitol.
The thickeners, which are preferably nonionic, can be chosen from modified or unmodified guar gums and cellulose gums, such as hydroxypropyl guar gum, cetylhydroxyethylcellulose, silicas such as, for example, Bentone Gel MiO sold by NL Industries or Veegum Ultra sold by Polyplastic.
Of course one skilled in the art will take care to select the optional complementary compound(s) and/or the amounts thereof such that the advantageous properties intrinsically associated with the composition in accordance with the invention are not, or are not substantially, adversely affected by the addition(s) envisaged.
The compositions according to the invention can be in the form of a lotion, a gel, a water-in-oil emulsion, an oil-in-water emulsion or a triple emulsion. They can also be in a vectorized form such as, for example, in the form of nanocapsules, liposomes, nanoemulsions or oleosomes.
These compositions may be used for application to the skin of the body, in particular to the skin of the face and the hands, to mucous and semi-mucous membranes or to the hair.
Such compositions can be in the form of care products or make-up products. In particular, they can be in the form of a care cream, a milk, a tonic, a cleansing and/or make-up-removing product, a mask, an erasing product, an exfoliant, a sunscreen product, a foundation, a tinted cream or a lipstick.